KRAS Q61H Mutation Confers Cancer Cells with Acquired Resistance to SHP2 Inhibition

Cancer cells with varied KRAS mutations exhibit different sensitivity to SHP2 inhibition. A recent work published in Nature Communications revealed the underlying drug resistance mechanism of cancer cells harboring KRAS Q61H mutation to SHP2 inhibitors (SHP2i). 1 This work showed that KRAS Q61H mutation renders cancer cells resistant to SHP2i via decoupling KRAS from SHP2-mediated upstream nucleotide exchange factors for (guanine nucleotide exchange factor [GEF])/GTPase activating protein (GAP) regulation, providing newinsightsintotreatingcancerswithKRASQ61Hmutations. KRAS, the most frequently mutated RASisoform, isa proto-oncogene that encodes small GTPase transductor protein. In response to upstream signals, KRAS can switch between inactive guanosine diphosphate (GDP) state and active guano-sinetriphosphate (GTP) stateby GEFs, such as Sonof Sevenless (SOS),orGAPs. 2 KRASmutations,primarilyatcodons12,13,or 61, account for 86% of RAS mutations. In particular, glutamine